Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases

ABSTRACT

The present invention relates to a method for treating ocular inflammatory diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/196,047 filed on Mar. 4, 2014, which claims the benefit ofU.S. Provisional Patent Application Ser. No. 61/773,773 filed on Mar. 6,2013, the disclosure of which is hereby incorporated in its entirety byreference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a method for treating ocularinflammatory diseases in a subject in need of such treatment, whichcomprises administering a pharmaceutical composition comprising atherapeutically effective amount of at least one agonist of Formylpeptide receptor 2 (FPR2).

2. Summary of the Related Art

The formyl peptide receptor (FPR) family is involved in host defenseagainst pathogens, but also in sensing internal molecules that mayprovide signals of cellular dysfunction. This family includes 3 membersin humans and one member of this family FPR2 (also known as FPRL-1,ALXA4) is a G protein-coupled receptor that is expressed predominantlyon inflammatory cells such as monocytes and neutrophils, as well as on Tcells and has been shown to play a critical role in leukocytetrafficking during inflammation and human pathology (Chiang N, Serhan CN, Dahlen, S, Drazen J M, Hay D W P, Rovati E, Shimizu T, Yokomizo T,Brink, C. The lipoxin receptor ALX: Potent ligand-specific andstereoselective actions in vivo. Pharmacological Reviews 2006; 58:463-519). FPR2 is an exceptionally promiscuous receptor that responds toa large array of exogenous and endogenous ligands, including serumamyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptidehumanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) andglucocotricoid-modulated protein annexin A1 (Chiang N, Serhan C N,Dahlen, S, Drazen J M, Hay D W P, Rovati E, Shimizu T, Yokomizo T,Brink, C. The lipoxin receptor ALX: Potent ligand-specific andstereoselective actions in vivo. Pharmacological Reviews 2006; 58:463-519). FPR2 transduces anti-inflammatory effects of LXA4 in manysystems, and has been shown to play a key role in the resolution ofinflammation (Dufton N, Perretti M. Therapeutic anti-inflammatorypotential of formyl peptide receptor agonists. Pharmacology &Therapeutics 2010; 127: 175-188). FPR2 knockout mice show exaggeratedinflammation in disease conditions as expected by the biological role ofthe receptor (Dufton N, Hannon R, Brancaleone V, Dalli J, Patel H B,Gray M, D'Aquisto F, Buckingham J C, Perretti M, Flower R J.Anti-inflammatory role of the murine formyl-peptide receptor 2:Ligand-specific effects on leukocyte responses and experimentalinflammation. Journal of Immunology 2010; 184: 2611-2619).

Activation of FPR2 by lipoxin A4 or its analogs and by Annexin I proteinhas been shown to result in anti-inflammatory activity by promotingactive resolution of inflammation which involves inhibition ofpolymorphonuclear neutrophils (PMNs) and eosinophils migration and alsostimulate monocyte migration enabling clearance of apoptotic cells fromthe site of inflammation in a nonphlogistic manner (Maderna P, Cottell DC, Toivonen T, Dufton N, Dalli J, Perretti M, Godson C. FPR2/ALXreceptor expression and internalization are critical for lipoxin A4 andannexin-derived peptide-stimulated phagocytosis. FASEB 2010; 24:4240-4249; Reville K, Cream J K, Vivers S, Dransfield I, Godson C.Lipoxin A4 redistributes Myosin IIA and Cdc42 in macrophages:Implications for phagocytosis of apoptotic leukocytes. Journal ofImmunology 2006; 176: 1878-1888). In addition, FPR2 has been shown toinhibit NK cytotoxicity and promote activation of T cells which furthercontributes to down regulation of tissue damaging inflammatory signals.FPR2/LXA4 interaction has been shown to be beneficial in experimentalmodels of ischemia reperfusion, angiogenesis, ocular inflammation suchas endotoxin-induced uveitis, and corneal wound healing (Serhan C.Resolution phase of inflammation: Novel endogenous anti-inflammatory andproresolving lipid mediators and pathways. Annual reviews of Immunology2007; 25: 101-137; Medeiros R, Rodrigues G B, Figueiredo C P, RodriguesE B, Grumman A Jr, Menezes-de-Lima O Jr, Passos G F, Calixto J B.Molecular mechanisms of topical anti-inflammatory effects of lipoxinA(4) in endotoxin-induced uveitis. Molecular Pharmacology 2008; 74:154-161; Gronert K, Maheshwari N, Khan N, Hassan I R, Dunn M,Schwartzmann M L. A role for the mouse 12/15-lipoxygenase pathways inpromoting epithelial wound healing and host defense. Journal ofBiological Chemistry 2005; 280: 15267-15278; Leedom A, Sullivan A B,Dong B, Lau D, Gronert K. Endogenous LXA4 circuits are determinants ofpathological angiogenesis in response to chronic injury. AmericanJournal of Pathology 2010; 176: 74-84; Gronert K. Lipoxins in the eyeand their role in wound healing. Prostaglandins, Leukotrienes andEssential Fatty Acids. 2005; 73: 221-229). Pharmaceutical utility oflipoxin A4 and its analogs are hampered by inherent physicochemicalproperties of the natural poly-olefinic natural product. Therefore,small molecule anti-inflammatory agonists of FPR2 would have a widevariety of therapeutic benefit in inflammatory disorders especially inthe eye. Targeting FPR2 selectively would also have benefits of reducedside effects as compared to more broad acting anti-inflammatories suchas steroids or NSAIDs which have significant side effects of elevatedIOP and delays in wound healing in the eye. FPR2 is also expressed inocular tissues in the cornea and also the posterior of eye, in additionto the inflammatory cells that migrate into the ocular tissues. FPR2thus represents an important novel pro-resolutionary molecular targetfor the development of new therapeutic agents in ocular diseases withexcessive inflammatory responses.

BRIEF DESCRIPTION OF THE INVENTION

The invention pertains to the ability of FPR2 agonists to exhibit ocularanti-inflammatory activity with chemical stability and suitable forocular delivery. These FPR2 compounds show good potency at the receptor,a subset of compounds is exemplified in the tables below, andimportantly, the FPR2 compounds are active topically, and thereforecould be administered in many forms, including but not limited to eyedrops. These compounds may also be administered directly or through alocal drug delivery device applied to ocular tissue, and via IV,intramuscularly, intrathecally, subcutaneously, orally, intravitreallyor intraperitoneally. These compounds will be useful for the treatmentof ocular inflammatory diseases including, but not limited to, uveitis,dry eye, keratitis, allergic eye disease, infectious keratitis, herpetickeratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis,and choroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, post-surgical corneal wound healing, conditions causedby laser, conditions caused by photodynamic therapy, wet and dryage-related macular degeneration (ARMD), conditions affecting theposterior part of the eye, such as maculopathies and retinaldegeneration including non-exudative age related macular degeneration,exudative age related macular degeneration, choroidalneovascularization, diabetic retinopathy (proliferative), retinopathy ofprematurity (ROP), acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi and Harada syndrome;vascular diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, cystoids macular edema,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby photodynamic therapy, photocoagulation, hypoperfusion during surgery,radiation retinopathy, and bone marrow transplant retinopathy;proliferative disorders such as proliferative vitreal retinopathy andepiretinal membranes, and proliferative diabetic retinopathy; infectiousdisorders such as ocular histoplasmosis, ocular toxocariasis, presumedocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis,retinal diseases associated with HIV infection, choroidal diseaseassociate with HIV infection, uveitic disease associate with HIVinfection, viral retinitis, acute retinal necrosis, progressive outerretinal necrosis, fungal retinal diseases, ocular syphilis, oculartuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis;genetic disorders such as retinitis pigmentosa, systemic disorders withaccosiated retinal dystrophies, congenital stationary night blindness,cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best'sdisease, pattern dystrophy of the retinal pigmented epithelium, X-linkedretinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy,Bietti's crystalline dystrophy, and pseudoxanthoma elasticum; retinaltears/holes such as retinal detachment, macular hole, and giant retinaltear; tumors such as retinal disease associated with tumors, congenitalhypertrophy of the retinal pigmented epithelium, posterior uvealmelanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis,combined hamartoma of the retina and retinal pigmented epithelium,retinoblastoma, vasoproliferative tumors of the ocular fundus, retinalastrocytoma, and intraocular lymphoid tumors; and miscellaneous otherdiseases affecting the posterior part of the eye such as punctate innerchoroidopathy, acute posterior multifocal placoid pigmentepitheliopathy, myopic retinal degeneration, and acute retinal pigmentepitheliitis, post-surgical corneal inflammation, blepharitis, MGD,glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative diseases of either the photoreceptorsor the retinal pigment epithelial (RPE).

In another aspect these compounds will be useful for the treatment ofocular inflammatory diseases associated with CNS disorders such asAlzheimer's disease, arthritis, sepsis, inflammatory bowel disease,cachexia, angina pectoris, rheumatoid arthritis and related inflammatorydisorders, alopecia, systemic inflammatory diseases such as stroke,coronary artery disease, obstructive airway diseases, HIV-mediatedretroviral infections, cardiovascular disorders including coronaryartery disease, neuroinflammation, neurological disorders, pain andimmunological disorders, asthma, allergic disorders, inflammation,systemic lupus erythematosus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 FPR2 agonists show potent anti-inflammatory activity inendotoxin-induced uveitis model in rats.

FIG. 2 FPR2 agonists show potent anti-inflammatory activity inendotoxin-induced uveitis model in rats.

FIG. 3 shows accelerated healing and re-epithelialization in a rabbitmodel of corneal wound as exemplified by Compound 3,{[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}aceticacid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating ocularinflammatory diseases in a subject in need of such treatment, whichcomprises administering a pharmaceutical composition comprising atherapeutically effective amount of at least one agonist of FPR2.

In another aspect, the invention provides the use of at least oneagonist of FPR2 for the manufacture of a medicament for the treatment ofan ocular inflammatory disease or condition mediated by FPR2 in amammal.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/668,835, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/668,835 forthe manufacture of a medicament for the treatment of an ocular diseaseor condition mediated by FPR2 in a mammal, provided that the compoundshave binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/668,835 fortreating an ocular disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/668,835are represented by Formula I:

wherein:

R¹ is sec-butyl, C₆₋₁₀ aryl, —CH2—(C₆₋₁₀)aryl, —CH₂-heterocycle, C₄₋₈cycloalkyl or C₃₋₈ cycloalkenyl or heterocycle;

R² is halogen or methyl;

R³ is halogen;

R⁴ is H, methyl or halogen;

R⁵ is OR⁶ or NH₂;

R⁶ is H or C₂₋₄ alkyl.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a pharmaceuticalcomposition, comprising a therapeutically effective amount of at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/523,579, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/523,579 forthe manufacture of a medicament for the treatment of an ocular diseaseor condition mediated by FPR2 in a mammal, provided that the compoundshave binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/523,579 fortreating an ocular disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/523,579are represented by Formula II:

wherein:

a is 1 and b is 0;

a is O and b is 1;

a is 1 and b is 1;

R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;

R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;

R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²; NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²; NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁵ is halogen, —CF₃ or —S(O)_(n)R¹⁴;

n is 0, 1 or 2;

R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²; NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²; NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl;

R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a pharmaceuticalcomposition, comprising a therapeutically effective amount of at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/673,800, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least a compoundas disclosed in U.S. patent application Ser. No. 13/673,800 for themanufacture of a medicament for the treatment of an ocular disease orcondition mediated by FPR2 in a mammal, provided that the compounds havebinding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least a compoundas disclosed in U.S. patent application Ser. No. 13/673,800 for treatingan ocular disease or condition mediated by FPR2 in a mammal, providedthat the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/673,800are represented by Formula Ill:

wherein:

R¹ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;

R² is halogen, optionally substituted C₁₋₈ alkyl, CF₃, OR⁹, C(O)R¹⁰,NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;

R³ is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈ cycloalkenyl,optionally substituted C₆₋₁₀ aryl, optionally substituted heterocycle,or together with R⁵ forms a 10- or 11-membered polycyclic ring which isoptionally substituted;

R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl;

optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈cycloalkenyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedheterocycle, or together with R⁵ forms a spiro monocyclic or polycyclic,carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 memberring which is optionally substituted;

R⁵ is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈ cycloalkenyl,optionally substituted C₆₋₁₀ aryl, optionally substituted heterocycle,or together with R⁴ forms a spiro monocyclic or polycyclic, carbocyclicor heterocyclic, saturated or unsaturated 5 to 10 member ring which isoptionally substituted or together with R³ forms a 5 or 6 member ringwhich is optionally substituted;

R⁶ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;

R⁷ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;

R⁸ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;

R⁹ is hydrogen, C(O)(C₁₋₈ alkyl) or optionally substituted C₁₋₈ alkyl;

R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl, O(C₁₋₈ alkyl),NR¹¹R¹² or OH;

R¹¹ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;

R¹² is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;

R¹³ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;

R¹⁴ is hydrogen, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₁₋₈ alkyl, C(O)(C₁₋₈ alkyl) or SO₂(C₁₋₈ alkyl);

R¹⁵ is hydrogen, optionally substituted C₁₋₈ alkyl or O(C₁₋₈ alkyl);

R¹⁶ is OH, O(C₁₋₈ alkyl), (C₁₋₈ alkyl) or NR¹¹R¹²;

R¹⁷ is hydrogen, optionally substituted C₈₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;

R¹⁸ is hydrogen, C(O)(C₁₋₈ alkyl), optionally substituted C₆₋₁₀ aryl, oroptionally substituted C₁₋₈ alkyl;

R¹⁹ is hydrogen, C(O)(C₁₋₈ alkyl), optionally substituted C₆₋₁₀ aryl oroptionally substituted C₁₋₈ alkyl;

R²⁰ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;

R²¹ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;

n is 1, 2, 3, 4, or 5;

m is 1, 2, 3, 4, or 5.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/765,527, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/765,527 forthe manufacture of a medicament for the treatment of an ocular diseaseor condition mediated by FPR2 in a mammal, provided that the compoundshave binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/765,527 fortreating an ocular disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/765,527are represented by Formula IV:

wherein:

R¹ is hydrogen, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈ cycloalkyl, substitutedor unsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted C₆₋₁₀ aryl, or together withR² can form an optionally substituted cyclobutyl;

R² is isopropyl or together with R³ can form a substituted orunsubstituted 3 to 6 member ring heterocycle or together with R¹ canform an optionally substituted cyclobutyl, cyclopropyl; and

R³ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstitutedheterocycle, substituted or unsubstituted C₆₋₁₀ aryl or together with R²can form a substituted or unsubstituted 3 to 6 member ring heterocycle.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a therapeuticallyeffective amount of a pharmaceutical composition, comprising at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/409,228, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/409,228 forthe manufacture of a medicament for the treatment of an ocular diseaseor condition mediated by FPR2 in a mammal, provided that the compoundshave binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/409,228 fortreating an ocular disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/409,228are represented by Formula V:

wherein:

“

” is a single bond or a double bond;

“

” is a single bond or a double bond;

R¹ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or hydroxyl;

R² is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or hydroxyl;

R³ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀ aryl or hydroxyl;

R⁴ is H or C(O)R¹²;

R⁵ is H, —OC₁₋₆ alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl or —C₂₋₆alkynyl;

R⁶ is H, —OC₁₋₆ alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl or —C₂₋₆alkynyl;

Y is O or S;

X is O, NR, or CH₂;

R^(a) is C₆₋₁₀ aryl,

heteroaryl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or H;

R^(b) is halogen;

c is 0, 1 or 2;

is

R⁷ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, hydroxyl, cyano, —OC₁₋₆alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl;

R⁸ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, cyano, —OC₁₋₆ alkyl, —SC₁₋₆alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²; NR¹³R¹⁴, C₃₋₈cycloalkenyl or C₃₋₈ cycloalkyl;

R⁹ is H, —S(O)₂R¹¹, —OC₁₋₆ alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆alkenyl, —C₂₋₆ alkynyl, C(O)R¹²; C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl;

R¹⁰ is —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or C₃₋₈ cycloalkenyl;

R¹¹ is H, hydroxyl, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;

R¹² is H, hydroxyl, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,NR¹³R¹⁴ or —OC₁₋₆ alkyl;

R¹³ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl SO₂R¹¹ orC(O)R¹⁵,

R¹⁴ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkenyl, aryl, heterocycle or C₃₋₈cycloalkyl;

R¹⁵ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl; and

R is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl;

with the provisos:

when “

” is a double bond then R⁵ is void; and

when “

” is a double bond R⁶ is void.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a pharmaceuticalcomposition, comprising a therapeutically effective amount of at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/370,472, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/370,472 forthe manufacture of a medicament for the treatment of an ocular diseaseor condition mediated by FPR2 in a mammal, provided that the compoundshave binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/370,472 fortreating an ocular disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent application Ser. No.13/370,472 are represented by Formula VI:

wherein:

A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;

R¹⁷ is C₁₋₆ alkyl or

B is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;

R¹ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R² is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R³ is H, C₁₋₆ alkyl or C₃₋₈ cycloalkyl;

R⁴ is H, C₁₋₆ alkyl or C₃₋₈ cycloalkyl;

R^(5a) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R^(5b) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R^(5c) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R^(5d) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R⁶ is H, —S(O)₂R¹¹, —C₁₋₆ alkyl, —(CH₂)_(n) NR¹³R¹⁴, —(CH₂)_(m),heterocycle, C(O)R¹²; NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, orheterocycle;

R⁷ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R⁸ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R⁹ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

R¹⁰ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²;NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

X is O or S,

Y is O or S,

R¹¹ is H, hydroxyl, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl or NR¹³R₁₄;

R¹² is H, hydroxyl, —C₁₋₆ alkyl, hydroxyl, C₃₋₈ cycloalkyl, NR¹³R¹⁴ or—OC₁₋₆ alkyl;

R¹³ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, SO₂R¹¹ or C(O)R¹⁶;

R¹⁴ is H, —C₁₋₆ alkyl or C₃₋₈ cycloalkyl;

R¹⁵ is —C₁₋₆ alkyl, or C₃₋₈ cycloalkyl;

R¹⁶ is H, —C₁₋₆ alkyl or C₃₋₈ cycloalkyl;

n is 1-4; and

m is 1-4.

In another aspect, the invention provides a method for treating ocularinflammatory diseases, which comprises administering a pharmaceuticalcomposition, comprising a therapeutically effective amount of at leastone agonist of FPR2 as disclosed in U.S. patent application Ser. No.13/863,934, provided that the compounds have binding activity at theFPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/863,934 forthe manufacture of a medicament for the treatment of an ocular diseaseor condition mediated by FPR2 in a mammal, provided that the compoundshave binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/863,934 fortreating an ocular disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent application Ser. No.13/863,934 are represented by Formula VII:

wherein:

n is 0 or 1;

R¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹²; CN or NO₂;

R² is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹²; CN or NO₂;

R³ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹²; CN, NO₂, CF₃,S(O)R¹⁵ or S(O)₂R¹⁶;

R⁴ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹²; CN or NO₂;

R⁵ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, SR¹¹, —C(O)R¹²; CN or NO₂;

R⁶ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₃₋₈ cycloalkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₈ cycloalkenyl or —CH₂R¹⁹;

R⁷ is substituted or unsubstituted heterocycle, —SR¹¹, —NR⁸R⁹,—N(H)C(O)N(H)S(O)₂R¹⁹, —BR¹³R¹⁴, —S(O)R¹⁵, —C(O)N(H)(CN),—C(O)N(H)S(O)₂R¹⁹, —S(O)(N)(PO₃H₂)—, —S(O)₂R¹⁶ or —P(O)R₁₇R₁₈;

R⁸ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;

R⁹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;

R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl or —CF₃,

R¹² is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, hydroxyl,—OR²⁴ or —NR⁸R⁹;

R¹³ is —OR²²;

R¹⁴ is —OR²³;

R¹⁵ is substituted or unsubstituted C₁₋₈ alkyl;

R¹⁶ is substituted or unsubstituted C₁₋₈ alkyl, —NR⁸R⁹ , —NHS(O)₂R¹⁹ orhydroxyl;

R¹⁷ is OR¹⁰ or NR⁸R⁹;

R¹⁸ is OR¹⁰ or NR⁸R⁹;

R¹⁹ is substituted or unsubstituted heterocycle, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₆₋₁₀ arylor substituted or unsubstituted C₃₋₈ cycloalkenyl;

R²⁰ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;

R²¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;

R²² is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, or togetherwith R²³ can form a cycle;

R²³ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, or togetherwith R²² can form a cycle;

R²⁴ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms. One methylene(—CH₂—) group, of the alkyl group can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate,amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl, by a divalentheterocycle, or by a divalent aryl group. Alkyl groups can have one ormore chiral centers. Alkyl groups can be independently substituted byhalogen atoms, hydroxyl groups, cycloalkyl groups, amino groups,heterocyclic groups, aryl groups, carboxylic acid groups, phosphonicacid groups, sulphonic acid groups, phosphoric acid groups, nitrogroups, amide groups, sulfonamide groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen atoms, sulfonylC₁₋₈ alkyl groups, sulfoxide C₁₋₈ alkyl groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₈ alkyl groups,—C₁₋₈ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketonegroups, alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkylgroups or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having at least one double bond. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be independentlysubstituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitrogroups, cyano groups, —C₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₆alkyl groups, —C₂₋₆ groups, —C₂₋₆ alkynyl groups, ketone groups,alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups orhydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group, ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₆ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected form oxygen, nitrogen,sulfur, or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₈ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms, by removal of one hydrogen atom. Aryl can be substituted byhalogen atoms, sulfonyl C₁₋₆ alkyl groups, sulfoxide C₁₋₆ alkyl groups,sulfonamide groups, carboxcylic acid groups, C₁₋₆ alkyl carboxylates(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₆ alkylgroups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups,—C₂₋₆ alkynyl groups, ketone groups, aldehydes, alkylamino groups, aminogroups, aryl groups, C₃₋₈ groups or hydroxyl groups. Aryls can bemonocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —(CO)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂—”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

In another aspect, agonists of FPR2 are compounds selected from Table 1:

TABLE 1 FPR2 Ga16-CHO EC₅₀ Structure IUPAC name (efficacy)

2-({[(4- chlorophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid 110nM (1.0)

(2S)-2-({[(4- methoxyphenyl)amino]carbonyl}amino)- 3-phenylpropanoicacid 1754 nM (0.90)

(2S)-3-phenyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl)amino]propanoic acid 120 nM (0.97)

(2S)-2-({[(3,4- dichlorophenyl)amino]carbonyl}amino)- 3-phenylpropanoicacid 10 μM (0.57)

(2S)-2-({[(4- nitrophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid574 nM (0.82)

3-phenyl-2-[({[4- (trifluoromethoxy)phenyl]amino}carbonyl)amino]propanoic acid 1572 nM (0.79)

2-({[(3,4- dimethoxyphenyl)amino]carbonyl} amino)-3-phenylpropanoic acid2793 nM (0.72)

methyl 2-({[(4- iodophenyl)amino]carbonyl}amino)- 3-phenylpropanoate14.3 nM (1.0)

(2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid31 nM (1.0)

(2R)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid1819 nM (0.99)

3-phenyl-2-{[(pyridin-3- ylamino)carbonyl]amino}propanoic acid >10000 nM

(2S,3S)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-methylpentanoicacid 4.1 nM (0.89)

(2S)-({[(4- bromophenyl)amino]carbonyl}amino) (phenyl)acetic acid 25.8nM (0.94)

2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-(1H-indol-3-yl)propanoicacid 67.0 nM (0.89)

(2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-methylbutanoic acid72 nM (0.91)

(2S)-2-({[(4-bromo-2- fluorophenyl)amino]carbonyl}amino)-3-methylbutanoic acid 152 nM (0.91)

US 2005/0137230 A1 and U.S. Pat. No. 7,820,673 disclose inhibitors ofcoagulation Factor Xa and can be employed for the prophylaxis and/ortherapy of thromboembolic diseases and/or the treatment of tumors.2-({[(4-chlorophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S)-2-({[(4-methoxyphenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S)-3-phenyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)amino]propanoicacid, methyl2-({[(4-iodophenyl)amino]carbonyl}amino)-3-phenylpropanoate,(2S)-2-({[(4-bromophenyl) amino]carbonyl}amino)-3-phenylpropanoic acid,(2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,are intermediates in the synthesis of urea derivatives as activatedblood coagulation factor X (FXa) inhibitors.

JP 63232846 discloses the resolution of N-(p-bromophenylcarbamyl)derivatives((2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S,3S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylpentanoicacid,2-({[(4-bromophenyl)amino]carbonyl}amino)-3-(1H-indol-3-yl)propanoicacid, (2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylbutanoicacid) on HPLC column with novel chromatographic chiral stationaryphases.

Journal of Chromatography (1987), 404(1), 117-22 and Chromatographia(1987), 23(10), 727-30 describe the resolution of p-Bromophenylcarbamylderivatives of enantiomeric protein amino acids((2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid),on novel chiral stationary phase by elution with an aqueous mobilephase.

Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis(1972), 272(4), 667-71 describes compound(2S)-2-({[(4-nitrophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid)in poly(uridylic acid)-dependent binding of paranitrophenyl-carbamyl-phenylalanyl tRNA.

In another aspect, agonists of FPR2 are compounds selected from Table 2:

TABLE 2 FPR2 Ga16-CHO EC₅₀ Structure IUPAC name (efficacy)

1-(4-chlorophenyl)-3-(2,4-dioxo- 1,3-diazaspiro[4,5]decan-3-yl) urea 49nM (0.98)

1-(4-chlorophenyl)-3-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1- yl)urea157 nM (0.96)

1-[4-methyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1-yl]-3- phenylurea223 nM (1.0)

1-(8-methyl-2,4-dioxo-1,3- diazaspiro[4,5]decan-3-yl)-3- (p-tolypurea363 nM (0.91)

1-(2-fluorophenyl)-3-[4-methyl- 2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 258 nM (0.94)

Compounds of Table 2 are available from Chemical Libraries such asAurora Fine Chemicals.

In another aspect, agonists of FPR2 are compounds selected from Table 3:

TABLE 3 FPR2 Ga16-CHO EC₅₀ Structure IUPAC name (efficacy)

N-(4-bromophenyl)-2-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)acetamide719 nM (0.94)

N-(4-bromophenyl)-2-(4,4-diethyl- 2,5-dioxoimidazolidin-1-yl)acetamide96 nM (0.98)

N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.5]dec-3-yl)acetamide738 nM (0.89)

N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.4]non-3-yl)acetamide322 nM (0.96)

N-(4-bromophenyl)-2-(2,5-dioxo-4,4- dipropylimidazolidin-1-yl)acetamide645 nM (0.98)

N-(4-bromophenyl)-2-(4-ethyl-2,5- dioxo-4-phenylimidazolidin-1-yl)acetamide 523 nM (0.83)

N-(4-bromophenyl)-2-(4-cyclopropyl- 4-methyl-2,5-dioxoimidazolidin-1-yl)acetamide 166 nM (0.84)

N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.6]undec-3-yl)acetamide679 nM (0.96)

N-(4-bromophenyl)-2-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1-yl)acetamide 485 nM (1.0)

N-(4-chlorophenyl)-2-(4,4-diethyl- 2,5-dioxoimidazolidin-1-yl)acetamide314 nM (0.79)

2-(4,4-diethyl-2,5-dioxoimidazolidin- 1-yl)-N-(4-fluorophenyl)acetamide2771 nM (0.67)

N-(4-bromophenyl)-2-[4-methyl-2,5- dioxo-4-(2-phenylethyl)imidazolidin-1-yl]acetamide 860 nM (0.88)

N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-4,7-methano-2H-isoindole-2-acetamide 575 (0.90)

N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-2H-isoindole-2-acetamide 395 (0.98)

The compounds of Table 3 are available from Chemical Libraries such asChemical Block Ltd.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of the FPR2.

Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

Therapeutic utilities of the FPR2 are ocular inflammatory diseasesincluding, but not limited to, wet and dry age-related maculardegeneration (ARMD), uveitis, dry eye, keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy(proliferative), retinopathy of prematurity (ROP), acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; infectious keratitis, herpetickeratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis,and choroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-andHarada syndrome; vascular diseases/exudative diseases such as retinalarterial occlusive disease, central retinal vein occlusion, cystoidsmacular edema, disseminated intravascular coagulopathy, branch retinalvein occlusion, hypertensive fundus changes, ocular ischemic syndrome,retinal arterial microaneurysms, Coat's disease, parafovealtelangiectasis, hemi-retinal vein occlusion, papillophlebitis, centralretinal artery occlusion, branch retinal artery occlusion, carotidartery disease (CAD), frosted branch angiitis, sickle cell retinopathyand other hemoglobinopathies, angioid streaks, familial exudativevitreoretinopathy, and Eales disease; traumatic/surgical conditions suchas sympathetic ophthalmia, uveitic retinal disease, retinal detachment,trauma, post-surgical corneal wound healing, conditions caused by laser,conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (POHS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with accosiated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, asthma, allergic disorders, inflammation, systemic lupuserythematosus, psoriasis, CNS disorders such as Alzheimer's disease,arthritis, sepsis, inflammatory bowel disease, cachexia, anginapectoris, post-surgical corneal inflammation, blepharitis, MGD, dermalwound healing, burns, rosacea, atopic dermatitis, acne, psoriasis,seborrheic dermatitis, actinic keratoses, viral warts, photoagingrheumatoid arthritis and related inflammatory disorders, alopecia,glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative disease of either the photoreceptorsor the RPE (Perretti, Mauro et al. Pharmacology & Therapeutics 127(2010) 175-188.)

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated bythe modulation of FPR2: including, but not limited to the treatment ofwet and dry age-related macular degeneration (ARMD), diabeticretinopathy (proliferative), retinopathy of prematurity (ROP), diabeticmacular edema, uveitis, dry eye, retinal vein occlusion, cystoidsmacular edema, glaucoma, branch vein occlusion, Best's vitelliformmacular degeneration, retinitis pigmentosa, proliferativevitreoretinopathy (PVR), and any other degenerative disease of eitherthe photoreceptors or the RPE.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the FPRL-1receptor. Such methods can be performed, for example, by administeringto a subject in need thereof a therapeutically effective amount of atleast one compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereisomers thereof.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions containing invention compounds may be in aform suitable for topical use, for example, as oily suspensions, assolutions or suspensions in aqueous liquids or nonaqueous liquids, or asoil-in-water or water-in-oil liquid emulsions.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable salt thereof, asan active ingredient with conventional ophthalmically acceptablepharmaceutical excipients and by preparation of unit dosage suitable fortopical ocular use. The therapeutically efficient amount typically isbetween about 0.001 and about 5% (w/v), preferably about 0.001 to about2.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventionalpharmaceutically acceptable preservatives, stabilizers and surfactants.Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar manner, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pH adjustorq.s. pH 4.5-7.8 antioxidant as needed surfactant as needed purifiedwater to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses. Especially preservative-free solutions are oftenformulated in non-resealable containers containing up to about ten,preferably up to about five units doses, where a typical unit dose isfrom one to about 8 drops, preferably one to about 3 drops. The volumeof one drop usually is about 20-35 μl.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of FPR2. Thus, infurther embodiments of the invention, there are provided methods fortreating a disorder associated with modulation of FPR2. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

Materials and Methods

FPR2 agonists would be expected to have significant effects in manydifferent types of ocular inflammation, but have been exemplified bydemonstrating anti-inflammatory activity in endotoxin-induced uveitis inrats (FIGS. 1 and 2). Anti-inflammatory activity in this model has beenexemplified with the FPR2 agonists described in Table 4.

FLIPR: HEK-Gα16 cells stably expressing the human FPR2 receptor wasutilized. Cells were plated into 384-well poly-D-lysine coated plates ata density of 18,000 cells per well one day prior to use. The growthmedia was DMEM medium supplemented with 10% fetal bovine serum (FBS), 1%antibiotic-antimycotic, 50 μg/ml hygromycin, and 400 μg/ml geneticin. Onthe day of the experiment, the cells were washed twice with Hank'sBalanced Salt Solution supplemented with 20 mM HEPES (HBSS/hepesbuffer). The cells were then dye loaded with 2 μM Fluo-4 diluted in theHBSS/Hepes buffer and incubated at 37° C. for 40 minutes. Extracellulardye was removed by washing the cell plates four times prior to placingthe plates in the FLIPR (Fluorometric Imaging Plate Reader, MolecularDevices). Ligands were diluted in HBSS/Hepes buffer and prepared in384-well microplates. Data for Ca⁺² responses were obtained in relativefluorescence units.

TABLE 4 Com- pound FPR2 num- EC₅₀ ber Structure IUPAC name (efficacy) 1

1-(4-bromophenyl)-3-[4-ethyl- 2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 3.0 (0.96) 2

{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}pentanoyl]amino}acetic acid2 (0.91) 3

{[(2S,3S)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methylpentanoyl]amino}acetic acid 1.98 (1.0) 4

1-(4-bromophenyl)-3-[4-ethyl- 2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 6.7 (0.90) 5

(2S,3S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 3-methylpentanoicacid 31 (0.96) 6

2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4-methylpentanoyl]amino}-2- methylpropanoic acid 1.66 (0.91) 7

{[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid 3.57 (1.0) 8

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid 0.78 (0.78) 9

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4- methylpentanoic acid 5.95(0.77) 10

2-{[(4- bromophenyl)carbamoyl]amino}-N- (2-oxoazepan-3-yl)-3-phenylpropanamide 11 nM (0.89) 11

3-[(4- iodophenyl)carbamoyl] spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2- carboxylic acid 1.6 nM (1.00) 12

3-[(4- bromophenyl)carbamoyl] spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2- carboxylic acid 4 nM (0.97) 13

1-(4-acetylphenyl)-3-{3-(4- cyanophenyl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo- 1,2,3,4-tetrahydroisoquinolin- 7-yl}urea 11nM (0.80) 14

rel-(2R,3S)-3-[(4- bromophenyl)carbamoyl] spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2-carboxylic acid 4 nM (0.90) 15

3-[(4- iodophenyl)carbamoyl] spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2-carboxylic acid 0.60 nM (0.87) 16

1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfanyl)phenyl]urea 2.5 nM(0.70) 17

1-{3-(4-cyanophenyl)-2-[2- (1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3- [4-(methylsulfanyl)phenyl]urea 5.5 nM(0.92) 18

1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfonyl)phenyl]urea 10 nM(0.86) 19

1-{3-(4-cyanophenyl)-2-[2- (1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3- [4-(methylsulfonyl)phenyl]urea 20 nM(1.00) 20

3-[(4-iodophenyl)carbamoyl]- 7-(propan-2- ylidene)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid 11 nM (0.94) 21

3-[(4- bromophenyl)carbamoyl]-7,7- dimethylbicyclo[2.2.1]heptane-2-carboxylic acid 10 nM (0.85) 22

3-[(4- iodophenyl)carbamoyl]-7,7- dimethylbicyclo[2.2.1]heptane-2-carboxylic acid 1.7 nM (0.97) 23

1-{3-(furan-2-yl)-2-[2-(1H- imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin- 7-yl}-3-[4- (methylsulfanyl)phenyl]urea19 nM (0.83) 24

1-{3-(5-fluoropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfinyl)phenyl]urea 11.8 nM (0.93) 25

1-{3-(5-fluoropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 10.5 nM (1.0) 26

N-(4-bromophenyl) spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2,3- dicarboxamide 4.8 nM (0.91) 27

1-{3-(5-chlorofuran-2-yl)-2-[2- (1H-imidazol-4-yl)ethyl]-1- oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3- [4-(methylsulfanyl)phenyl]urea 17 nM(0.81) 28

1-{3-(6-chloropyridin-3-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 6.3 nM (0.89) 29

3-{[4- (methylsulfanyl)phenyl]carbamoyl} spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2- carboxylic acid 7 nM (0.96) 30

N-(4-bromophenyl) spiro[bicyclo[2.2.1]heptane- 7,1′-cyclopropane]-2,3-dicarboxamide 2.5 nM (0.96) 31

3-{[4- (methylsulfanyl)phenyl]carbamoyl}spiro[bicyclo[2.2.1]heptane-7,1′- cyclopropane]-5- ene-2-carboxylic acid14 nM (0.85) 32

1-{3-(5-chloropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 13.5 nM (0.91) 33

1-{3-(5-chloropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 9.5 nM (0.99) 34

N-(4-bromophenyl)-7,7- dimethylbicyclo[2.2.1]heptane- 2,3-dicarboxamide15 nM (0.83) 35

N-(4-iodophenyl)-7,7- dimethylbicyclo[2.2.1]heptane- 2,3-dicarboxamide2.6 nM (0.81) 36

(+)1-[(3R)-2-(3-aminopropyl)- 3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin- 7-yl]-3-[4- (methylsulfanyl)phenyl]urea3.3 nM (0.97) 37

7,7-dimethyl-N-[4-(methylsulfanyl) phenyl]bicyclo[2.2.1]heptane-2,3-dicarboxamide 17 nM (0.85) 38

N-(4-iodophenyl) spiro[bicyclo[2.2.1]heptane- 7,1′-cyclopropane]-2,3-dicarboxamide 1.9 nM (0.95) 39

N-(4-iodophenyl) spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2,3- dicarboxamide 1.6 nM (0.90) 40

(+) tert-butyl {3-[(3R)-3-(4- cyanophenyl)-7-({[4-(methylsulfinyl)phenyl] carbamoyl}amino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl] propyl}carbamate 103 nM (0.91) 41

(+) 1-[(3R)-2-(3- aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfinyl)phenyl]urea 10.6 nM(0.94) 42

1-[2-(3-aminopropyl)-3- methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfanyl)phenyl]urea 15 nM(1.00) 43

1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- (4-iodophenyl)urea 13.7 nM (0.94) 44

(+) (2S,3R)-3-[(4-bromophenyl) carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2- carboxylic acid <1 nM (0.98) 45

(−) N-(4- bromophenyl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide <1 nM (0.91) 46

N-(4-bromophenyl)-N′- methylspiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide 8.5 nM (1.0) 47

N-(4-bromophenyl)-N′- ethylspiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide 9.3 nM (1.0) 48

N-(4-bromophenyl)-N′- (propan-2- yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide 6.7 nM (1.0) 49

1-(4-bromophenyl)-3-(4,4- diethyl-2,5-dioxoimidazolidin- 1-yl)urea 11.5nM (0.98) 50

1-(4-bromo-2-fluorophenyl)- 3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea 15.7 nM (1.0) 51

(2S)-2-{[(4- iodophenyl)carbamoyl]amino}- 3-phenylpropanoic acid 14.5 nM(1.0) 52

1-(4-bromophenyl)-3-(2,4- dioxo-1,3-diazaspiro[4.5]dec- 3-yl)urea 15.1nM (1.0) 53

(2S,3S)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-methylpentanoic acid12.9 nM (0.9) 54

1-(4-bromophenyl)-3-[4- methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 5.1 nM (0.87) 55

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetic acid 7.7 nM (0.99) 56

3-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-3- phenylpropanoyl]amino}propanoic acid 18 nM (0.98) 57

(+) 1-(4-bromophenyl)-3-[4- methyl-2,5-dioxo-4-(2-phenylethypimidazolidin-1- yl]urea 3.2 nM (0.93) 58

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-hydroxyethyl)-3-phenylpropanamide 7.0 nM (0.86) 59

{[(2S,3S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid 5.5 nM (0.95) 60

(2S,3S)-N-(2-amino-2- oxoethyl)-2-{[(4- bromophenyl)carbamoyl]amino}-3-methylpentanamide 4.6 nM (0.91) 61

1-(4-bromo-2-fluorophenyl)- 3-[4-2,5-dioxo-4-(propan-2-yl)imidazolidin-1- yl]urea 9.2 nM (0.97) 62

(2S,3S)-N-(2-amino-2- oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}- 3-methylpentanamide 10.3 nM (1.0) 63

2S,3S)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-methyl-N-(2-oxopropyl)pentanamide 10.5 nM (0.97) 64

1-(4-bromophenyl)-3-[2,5- dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea 3.8 nM (1.0) 65

1-(4-bromophenyl)-3-(4,4- dicyclopropyl-2,5- dioxoimidazolidin-1-yl)urea14.3 nM (1.0) 66

(+)1-(4-bromophenyl)-3-[4- ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 4.3 nM (0.96) 67

(−)1-(4-bromophenyl)-3-[4- ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 3.3 nM (1.0) 68

(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- N-(2-oxopropyl)-3-phenylpropanamide 12.4 nM (0.94) 69

1-(4-bromo-2-fluorophenyl)- 3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea 13.4 nM (0.91) 70

(2S)-2-{[(4- bromophenyl)carbamoyl]amino} pentanoic acid 7.1 nM (1.0) 71

(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3- phenylpropanamide 15.6 nM (0.98) 72

methyl{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate 16.4 nM (0.86) 73

propan-2-yl {[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate 14.5 nM (1.0) 74

{[(2S)-2-+{[(4-bromo-2- fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid 4.1 nM (0.91) 75

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-hydroxyethyl)-4-methylpentanamide 13.5 nM (0.76) 76

1-(4-bromophenyl)-3-{4-[2- (furan-2-yl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1- yl}urea 5.2 nM (0.99) 77

(2S)-N-(2-amino-2-oxoethyl)- 2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanamide 1.1 nM (1.0) 78

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methyl-N-(2-oxopropyl)pentanamide 4.7 nM (0.82) 79

(2S)-N-(2-amino-2-oxoethyl)- 2-{[(4- bromophenyl)carbamoyl]amino}pentanamide 2.5 nM (0.97) 80

1-(4-bromophenyl)-3-{4-[2-(2- fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1- yl}urea 14.3 nM (99) 81

(2S)-N-(2-amino-2-oxoethyl)- 2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino} pentanamide 5.2 nM (0.96) 82

1-(4-bromophenyl)-3-{4-[2-(4- fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1- yl}urea 16.3 nM (1.0) 83

1-(4-bromophenyl)-3-{4-[2-(3- fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1- yl}urea 11.1 nM (1.0) 84

(2S)-N-(2-amino-2-oxoethyl)- 2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}- 4-methylpentanamide 4.5 nM (0.95) 85

(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-methyl-N-(2-oxopropyl)pentanamide 20 nM (0.99) 86

1-(4-bromophenyl)-3-{-[2-(4- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 13.3 nM (1.0) 87

(2S)-2-{[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} propanoic acid 12.1 nM (0.95) 88

1-(4-bromophenyl)-3-{4- methyl-2,5-dioxo-4-[2- (thiophen-2-yl)ethyl]imidazolidin-1-yl}urea 7.9 nM (0.94) 89

1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(4- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 8.7 nM (0.85) 90

(2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} propanoic acid 11.6 nM (1.0) 91

(2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3- methylbutanoic acid 1.7 nM (0.97) 92

(2S)-N-[(2S)-1-amino-3- methyl-1-oxobutan-2-yl]-2- {[(4-bromophenyl)carbamoyl]amino}- 4-methylpentanamide 5.8 nM (1.0) 93

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-hydroxy-2-methylpropyl)-4- methylpentanamide 2.5 nM (0.93) 94

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide 7.4 nM (0.96) 95

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2,3-dihydroxypropyl)-4-methylpentanamide 5.1 nM (0.98) 96

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-[(2R)-1-hydroxypropan-2-yl]-4- methylpentanamide 3.0 nM (1.0) 97

1-(4-bromophenyl)-3-{4- methyl-4-[2-(5-methylfuran-2- yl)ethyl]-2,5-dioxoimidazolidin-1-yl}urea 3.5 nM (0.95) 98

1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(3-fluoro-4- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 7.4 nM (0.91) 99

1-(4-bromophenyl)-3-{4-[2-(3- fluoro-4- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 8.0 nM (1.0) 100

tert-butyl (2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} pentanoate 13.0 nM (1.0) 101

(2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} pentanoic acid 1.0 nM (0.95) 102

(2S)-N-[(2S)-1-amino-1- oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}- 4-methylpentanamide 7.3 nM (0.99) 103

(2S)-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} (phenyl)ethanoic acid 9.1 nM (1.0) 104

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methyl-N-(1H-tetrazol-5-ylmethyl)pentanamide 2.3 nM (0.81) 105

ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} methyl)phosphonate 0.95 nM (0.88) 106

1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(2- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 4.0 nM (0.91) 107

1-(4-bromo-2-fluorophenyl)- 3-{4-[2-(3- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 2.2 nM (0.79) 108

1-(4-bromophenyl)-3-{4-[2-(3- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 2.1 nM (1.0) 109

1-(4-bromophenyl)-3-{4-[2-(2- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin- 1-yl}urea 0.97 nM (0.93) 110

2-{[(4- bromophenyl)carbamoyl]amino}- 2,4-dimethylpentanoic acid 19.4 nM(0.98) 111

[(2-{[(4- bromophenyl)carbamoyl]amino}- 2,4-dimethylpentanoyl)amino]acetic acid 19.1 nM (0.99) 112

diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} methyl)phosphonate 0.48 nM (0.95) 113

(2-{[(4- bromophenyl)carbamoyl]amino}- 2-ethylbutanoyl)amino]acetic acid18.7 nM (1.0) 114

diethyl ({[(2S,3S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino} methyl)phosphonate 2.9 nM (1.0) 115

ethyl hydrogen ({[(2S,3S)-2- {[(4- bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino} methyl)phosphonate 2.7 nM (0.88) 116

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-[(3-hydroxy-1,2-oxazol-5-yl)methyl]-4- methylpentanamide 12.0 nM (1.0) 117

diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl) phosphonate 0.27 nM (1.0) 118

diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino} methyl)phosphonate 16.1 nM (0.93) 119

diethyl (2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}ethyl) phosphonate 16.1 nM (0.97) 120

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-[2-(dimethylamino)-2-oxoethyl]-4- methylpentanamide 1.7 nM (0.99) 121

(2S)-2-{[(4- iodophenyl)carbamoyl]amino}- 4-methylpentanoic acid 4.0 nM(0.93) 122

(2R,3R)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-methylpentanoic acid 10μM (0.59) 123

ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl) phosphonate 1 nM (0.96) 124

{[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid 1.8 nM (1.0) 125

dipropan-2-yl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl) phosphonate 1.2 nM (1.0) 126

ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino} methyl)phosphonate 16.0 nM (1.0) 127

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methylpentanoyl]amino}methanesulfonic acid 2.0 nM (0.91) 128

(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl]carbamoyl} amino)pentanoicacid 16.8 nM (0.92) 129

propan-2-yl hydrogen {[(2- {[(4- bromophenyl)carbamoyl]amino}pentanoyl)amino]methyl} phosphonate 1.87 nM (0.89) 130

{[(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino} acetic acid 3.0 nM (1.0) 131

dipropan-2-yl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} methyl)phosphonate 4.0 nM (1.0) 132

1-(4-bromophenyl)-3-[4- (hydroxymethyl)-2,5-dioxo-4-(propan-2-yl)imidazolidin-1- yl]urea 16.2 nM (0.86) 133

2-[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2- hydroxyethyl)acetamide 2.7 nM (1.0) 134

diethyl ({[(2S)-4-methyl-2- ({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino} methyl)phosphonate 5.5 nM (0.97) 135

ethyl hydrogen ({[(2S)-4- methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl} amino)pentanoyl]amino}methyl)phosphonate 1.9 nM (0.91) 136

(2S)-4-methyl-N-(1H-tetrazol- 5-ylmethyl)-2-({[4-(trifluoromethyl)phenyl]carbamoyl} amino)pentanamide 3.7 nM (0.96) 237

{[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino} methanesulfonic acid 1.9 nM (0.99) 138

diethyl ({[(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino} methyl)phosphonate 3.5 nM (0.91) 139

2-methyl-2-{[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino} propanoic acid 2.5 nM (0.92) 140

tert-butyl (2S)-2-{[(4- bromophenyl)sulfamoyl]amino}- 4-methylpentanoateNA 141

methyl 2-[2-(1-{[(4- bromophenyl)carbamoyl]amino}- 4-ethyl-2,5-dioxoimidazolidin-4- yl)ethyl]benzoate 10.3 nM (0.92) 142

2-[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(1,3- dihydroxypropan-2-yl)acetamide 13.8 nM(0.92) 143

2-[2-(1-{[(4- bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4- yl)ethyl]benzoic acid 17.2 nM (1.0) 144

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino} acetic acid 6.3 nM (0.91) 145

3-({[-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)propanoic acid1.0 nM (1.0) 146

2-[2-(1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-ethyl-2,5-dioxoimidazolidin-4- yl)ethyl]benzoic acid 11.1 nM (1.0) 147

3-({[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4- yl]acetyl}amino)propanoic acid 3.9 nM (0.99) 148

2-[1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2- hydroxyethyl)acetamide 6.9 nM (0.98) 149

ethyl 3-[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]propanoate 6.6 nM (0.94) 150

{[2-{[(4- bromophenyl)carbamoyl]amino}- 3-(1H-indol-3-yl)propanoyl]amino}acetic acid 1.4 nM (0.98) 151

2-{2-[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4- yl]ethyl}benzoic acid 5.8 nM (1.0) 152

diethyl [2-({[1-{[(4- bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)ethyl]phosphonate 11 nM (1.0) 153

ethyl 3-{[(4- bromophenyl)carbamoyl]amino}- 2,4-dioxo-1,3-diazaspiro[4.5]decane-8- carboxylate 12 nM (0.99) 154

tert-butyl {[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl)amino} acetate 12 nM (0.85) 155

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl)amino} acetic acid 1.0 nM (1.0)

Immunohistochemistry: Chromogenic DAB immunohistochemistry withantibodies specific to FPR2 was used to determine localization in normalhuman, primate, and rat eyes. Anti-FPR2 antibody (Abcam) was used at adilution of 1:200 to detect FPR2 protein in all species.

Endotoxin-induced uveitis in rats: Uveitis is a harmful ocularinflammatory condition in humans. Anterior uveitis is a recurrentinflammatory disease and may have potentially blinding consequence. Thepathogenesis of the disease is poorly understood, and theanti-inflammatory therapy used is non-specific and is associated withsignificant complications. Animal models are key to understanding thedisease and testing novel therapies. A single low dose oflipopolysaccharide (LPS) in the footpad induces anterior uveitis inrats. This model known as endotoxin-induced uveitis serves as a usefulparadigm of human anterior uveitis. Male Lewis rats (260±25 grams) werepurchased from Charles River Laboratory. Rats were footpad-injected(hind left side) with 100 μl of 1 mg/ml LPS (List Biological Labs)solution (in sterile 0.9% saline). Test compounds were formulated in thevehicle consisting of sodium phosphate, dibasic heptahydrate, salts, CMCand sterile water. Compounds were topically (0.1-1%) or subcutaneously(10 mg/kg) dosed 2 hr after LPS. Animals were sacrificed at 24 hoursfollowing LPS injection. Aqueous humor was collected and analyzed todetermine inflammatory cell counts and total protein concentrations.

Alkali burn in rabbits: Corneal epithelium plays an important role inthe maintenance of corneal function and integrity. Prolonged cornealepithelial defects causes corneal opacity, neovascularization, bacterialinfection and visual loss. Corneal epithelial healing is a complexprocess involving inflammatory response to injury, cell proliferationand migration. Animal models of corneal injury are every useful to testnew anti-inflammatory and pro-wound healing therapies. New Zealand Whiterabbits weighing between 2.1 and 2.5 kg were anesthetized systemicallywith Ketamine/Xylazine (35/5 mg/kg) subcutaneously and topically withproparacaine (0.5%). The corneal epithelial wound in one eye was inducedwith a NaOH saturated filter paper containing 1.0 N NaOH for 30 seconds.The eyes were rinsed with sterile PBS. The corneal wound was confirmedby fluorescein staining with 10% sodium fluorescein (Science Lab Com)and slit lamp photography. Test compounds were formulated in the vehicledescribed above. For initial studies compounds were topically dosedthree times a day. Quantification of corneal wound areas was done usingImage J software where fluorescing stain green part was traced andconverted to total pixel.

The compounds below would be expected to have significant effects inmany different types of ocular inflammation, but have been exemplifiedby demonstrating anti-inflammatory activity in endotoxin-induced uveitisin rats (FIGS. 1 and 2). Anti-inflammatory activity in this model hasbeen exemplified with the following FPR2 agonists.

In this model the compounds show a strong anti-inflammatory activity inblocking the infiltration of neutrophils and protein into the anteriorchamber. In addition FPR2 agonists show accelerated healing andre-epithelialization in mouse models of corneal wound as exemplified bycompound{[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}aceticacid in (FIG. 3). These data demonstrate that FPR2 agonists are potentand efficacious anti-inflammatory agents suitable for ocular use indifferent models of ocular inflammation.

What is claimed is:
 1. A method of treating an ocular inflammatorydisease in a subject in need of such treatment, wherein the methodcomprises administering a pharmaceutical composition comprising atherapeutically effective amount of at least one formyl peptide receptor2 (FPR2) agonist to the subject; wherein the ocular inflammatory diseaseis selected from the group consisting of uveitis, dry eye, keratitis,allergic eye disease, infectious keratitis, herpetic keratitis, cornealangiogenesis, lymphangiogenesis, retinitis, choroiditis, acutemultifocal placoid pigment epitheliopathy, Behcet's disease,post-surgical corneal wound healing, wet age-related maculardegeneration (ARMD) and dry ARMD; and wherein the agonist is a compoundrepresented by Formula I, or a pharmaceutically acceptable salt thereof:

wherein: R¹ is sec-butyl, C₆₋₁₀ aryl, —CH₂—(C₆₋₁₀)aryl,—CH₂-heterocycle, C₄₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or heterocycle; R²is halogen or methyl; R³ is halogen; R⁴ is H, methyl or halogen; R⁵ isOR⁶ or NH₂; and R⁶ is H or C₂₋₄ alkyl; or wherein the agonist is acompound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 2. The method of claim 1,wherein the agonist is a compound of Formula I.
 3. The method of claim2, wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 4. The method of claim 1,wherein the agonist is a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 5. The method of claim 4,wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.